Investigators unveil metastatic prostate cancer’s genomic landscape

Localized prostate cancer that is diagnosed before it has a chance to spread typically responds well to surgery or radiation. But when a tumor metastasizes and sends malignant cells elsewhere in the body, the prognosis worsens. Better treatments for men with metastatic prostate cancer are urgently needed. In 2018, scientists advanced toward that goal by sequencing the entire metastatic cancer genome.

The newly revealed genomic landscape includes not just the active genes that make proteins, but also the vast stretches of DNA in between them that can also be functionally significant. Most of the genomic alterations were structural, meaning that DNA letters in the cells were mixed up, duplicated, or lost. A major finding was that the androgen receptor, which is a target for hormonal medications used when cancer returns after initial treatment, was often genetically amplified. That could explain why patients often become stubbornly resistant to hormonal therapies: if the androgen receptor is hyperactive, then the treatments can’t fully block its activity.

The research revealed many other sorts of alterations as well. For instance, DNA-repair genes such as BRCA2 and MMR were often defective. Cells rely on these genes to fix the genetic damage that afflicts them routinely every day, but with their functional loss, cancerous changes can follow. Cancer-driving oncogenes such as MYC were common, as were “tumor-suppressor” genes such as TP53 and CDK12, which ordinarily work to keep cancer at bay.

Metastatic prostate cancer differs from one man to another, and likewise, the frequency of these alterations varied among the more than 100 men who provided samples for analysis. By exploring the data, scientists can now develop new hypotheses for testing, and refine personalized treatment strategies to help men with this life-threatening disease.